Rational Design of Prevascularized Large 3D Tissue Constructs Using Computational Simulations and Biofabrication of Geometrically Controlled Microvessels
Rational Design of Prevascularized Large 3D Tissue Constructs Using Computational Simulations and Biofabrication of Geometrically Controlled Microvessels
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DOI：
10.1002/adhm.201500958
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发表时间：
2016-07-06
影响因子：
10
通讯作者：
Moretti, Matteo
中科院分区：
文献类型：
--
作者：
Arrigoni, Chiara;Bongio, Matilde;Moretti, Matteo
在临床相关三维组织结构的发展中的一个主要挑战是形成供氧、营养供应和废物清除的血管网络。为此，本研究实施了一种多模式方法来促进刚性纤维蛋白水凝胶中血管样结构的形成。已经进行了计算模拟，以确定在整个厚圆柱形水凝胶(高度8 mm，空置6 mm)中确保常氧条件的最容易的微通道配置，表明在我们的配置中，需要至少三个以非平面布置放置的微通道(600微米空置)。使用氧分布与微通道构型相同的小型水凝胶砖，本研究表明，在不同的培养条件下，间充质细胞和内皮细胞与添加Ang-1和VEGF的共培养可形成最发达的血管网络。然后将微通道水凝胶在相同的条件下静态和在生物反应器中培养7d。出乎意料的是，剪切力和常氧条件的结合不能促进三通道水凝胶中微血管网络的形成。不同的是，单独施加剪切力或常氧条件都会导致微血管生长。这些结果表明，要在工程结构中诱导血管生成，必须调节几个生化和生物物理参数之间的复杂相互作用。
A major challenge in the development of clinically relevant 3D tissue constructs is the formation of vascular networks for oxygenation, nutrient supply, and waste removal. To this end, this study implements a multimodal approach for the promotion of vessel-like structures formation in stiff fibrin hydrogels. Computational simulations have been performed to identify the easiest microchanneled configuration assuring normoxic conditions throughout thick cylindrical hydrogels (8 mm height, 6 mm empty set), showing that in our configuration a minimum of three microchannels (600 mu m empty set), placed in a non-planar disposition, is required. Using small hydrogel bricks with oxygen distribution equal to the microchanneled configuration, this study demonstrates that among different culture conditions, co-culture of mesenchymal and endothelial cells supplemented with ANG-1 and VEGF leads to the most developed vascular network. Microchanneled hydrogels have been then cultured in the same conditions both statically and in a bioreactor for 7 d. Unexpectedly, the combination between shear forces and normoxic conditions is unable to promote microvascular networks formation in three-channeled hydrogels. Differently, application of either shear forces or normoxic conditions alone results in microvessels outgrowth. These results suggest that to induce angiogenesis in engineered constructs, complex interactions between several biochemical and biophysical parameters have to be modulated.